Retinitis pigmentosa (RP) refers to a group of inherited degenerations of the photoreceptor cells (rods and cones) of the retina leading to visual loss and blindness. Mutations in any of a wide variety of genes can cause RP, including genes encoding proteins that are involved in phototransduction (the process by which the energy of a photon of light is converted in the photoreceptor cell outer segment into a neuronal signal), the visual cycle (production and recycling of vitamin A in the retina), photoreceptor structure, and transcription factors (Phelan and Bok, 2000).
RLBP1-associated retinal dystrophy is a rare form of RP caused by mutations in the retinaldehyde binding protein 1 (RLBP1) gene on chromosome 15. Mutations in this gene cause absence of or dysfunction of cellular retinaldehyde-binding protein (CRALBP), a protein that is important in the visual cycle (He et al 2009). CRALBP is expressed in retinal pigment epithelium (RPE) and Müller cells, ciliary epithelium, iris, cornea, pineal gland and a subset of oligodendrocytes of the optic nerve and brain (Saari et al 1997). CRALBP accepts 11-cis-retinol from the isomerase RPE65 and acts as a carrier of this substrate for 11-cis-retinol dehydrogenase (RDH5) to convert the substrate into 11-cis-retinal. The rate of chromophore regeneration is severely reduced in the absence of functional CRALBP (Travis et al 2007). The function of CRALBP outside the RPE is not well understood, but it has been suggested that CRALBP in the Müller cells supports a cone-specific visual pathway that permits cone cells to quickly adapt to a wide range of light intensities (Wang and Kefalov 2011).
RLBP1-associated retinal dystrophy is characterized by early severe night blindness and slow dark adaptation, followed by progressive loss of visual acuity, visual fields and color vision leading to legal blindness typically around middle adulthood. The fundus appearance is characterized by yellow or white spots in the retina. The reduction in visual acuity and visual field significantly impacts patients' quality of life (Burstedt and Mönestam, 2010).
The most common RLBP1 mutations leading to RLBP1-associated retinal dystrophy are recessive mutations, designated R234W and M226K (Golovleva I and Burstedt M 2012). RLBP1-associated retinal dystrophy caused by 1 or both of these recessive missense mutations is also known as Bothnia Dystrophy. Several other loss-of-function mutations in the RLBP1 gene have been reported to lead to RLBP1-associated retinal dystrophy. For example, splice-junction mutations in RLBP1 cause rod-cone dystrophy in Newfoundland. Currently there is no treatment available for RLBP1-associated retinal dystrophy (Eichers et al 2002).
The present invention is based in part on the discovery that expression of RLBP1 from recombinant adeno-associated viral vectors (rAAV) having a combination of selected promoter, AAV genome and capsid serotype provides a potent and efficacious treatment for RLBP1-associated retinal dystrophy.